SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model

Lieber et al., Nature Communications, doi:10.1038/s41467-022-32045-1

Jul 2022

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Roborovski dwarf hamster and in vitro study finding molnupiravir efficacy varied significantly by SARS-CoV-2 variant in the hamster model, in contrast to no significant difference seen in cultured cells and human organoids. Efficacy for omicron in the hamster model varied significantly based on biological sex.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.

Important missing comments or errors? Let us know.

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2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

3. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

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5. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

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8. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

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13. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Lieber et al., 29 Jul 2022, USA, peer-reviewed, 15 authors. Contact: rplemper@gsu.edu.

This Paper Molnupiravir All

Abstract: nature communications Article https://doi.org/10.1038/s41467-022-32045-1 SARS-CoV-2 VOC type and biological sex affect molnupiravir efﬁcacy in severe COVID-19 dwarf hamster model Received: 1 March 2022 Check for updates 1234567890():,; 1234567890():,; Accepted: 14 July 2022 Carolin M. Lieber1,5, Robert M. Cox 1,5, Julien Sourimant 1, Josef D. Wolf 1, Kate Juergens2, Quynh Phung2, Manohar T. Saindane3, Meghan K. Smith 3, Zachary M. Sticher 3, Alexander A. Kalykhalov3, Michael G. Natchus3, George R. Painter3, Kaori Sakamoto4, Alexander L. Greninger2 & Richard K. Plemper 1 SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efﬁcacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was signiﬁcant in males, but not females. The dwarf hamster model recapitulates mixed efﬁcacy of molnupiravir in human trials and alerts that beneﬁt must be reassessed in vivo as VOC evolve. By May 2022, SARS-CoV-2 has resulted in over 522 million cases and >6.2 million deaths worldwide1. Vaccines are widely available2,3, but recuring global infection waves have been fueled by limited longevity of vaccine-induced immunity, the hesitancy of population subgroups to vaccinate4,5, and increasingly contagious and/or vaccine-insensitive variants of concern (VOC) alpha (B.1.1.7 lineage), beta (B.1.351 lineage), gamma (P.1 lineage), delta (B.1.617.2 lineage), and omicron (B1.1.529 lineage)6,7. VOC delta was the prevalent circulating variant during Summer and Fall 2021 due to replication to high titers, prolonged shedding from infected individuals, and propensity to induce breakthrough infections in vaccinees8–10. Since its ﬁrst appearance in November 2021, VOC omicron has rapidly replaced delta as the dominant circulating strain in most geographical regions11, propelled by sharply reduced sensitivity to neutralizing antibodies directed against earlier lineages and greatly increased infectivity12. Although clinical signs associated with VOC omicron are typically milder than those of its predecessors, record-high daily infection rates have driven high absolute hospitalization numbers, creating an urgent need for therapeutics to improve disease management. Molnupiravir was the ﬁrst orally available SARS-CoV-2 inhibitor approved for outpatient use against COVID-1913. Intermediate results of the early months of a large efﬁcacy trial revealed an encouraging 50% reduction in hospitalizations in the treatment group, but later analysis of the full dataset showed only a 30% lower hospitalization rate overall14. Based on the geographical location of trial participants and VOC prevalence in the earlier versus later phase of the trial, an 1 Center for Translational Antiviral Research, Institute for Biomedical Sciences, Georgia State..

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SARS-CoV-2 is transmitted via contact and via the air ' 'between ferrets. Nat. Commun. 11, 3496 (2020).', 'journal-title': 'Nat. Commun.'}, { 'key': '32045_CR38', 'doi-asserted-by': 'publisher', 'first-page': '1169', 'DOI': '10.1126/science.368.6496.1169', 'volume': '368', 'author': 'M Enserink', 'year': '2020', 'unstructured': 'Enserink, M. Coronavirus rips through Dutch mink farms, triggering ' 'culls. Science 368, 1169 (2020).', 'journal-title': 'Science'}, { 'key': '32045_CR39', 'doi-asserted-by': 'publisher', 'first-page': '617', 'DOI': '10.1016/S0002-9343(70)80129-2', 'volume': '49', 'author': 'H Remmer', 'year': '1970', 'unstructured': 'Remmer, H. The role of the liver in drug metabolism. Am. J. Med. 49, ' '617–629 (1970).', 'journal-title': 'Am. J. Med.'}, { 'key': '32045_CR40', 'doi-asserted-by': 'publisher', 'first-page': '177', 'DOI': '10.1128/JCM.01881-16', 'volume': '55', 'author': 'AL Greninger', 'year': '2017', 'unstructured': 'Greninger, A. L. et al. Rapid metagenomic next-generation sequencing ' 'during an investigation of hospital-acquired human parainfluenza virus 3 ' 'infections. J. Clin. Microbiol. 55, 177–182 (2017).', 'journal-title': 'J. Clin. Microbiol.'}, { 'key': '32045_CR41', 'doi-asserted-by': 'publisher', 'unstructured': 'Addetia, A. et al. Sensitive recovery of complete SARS-CoV-2 genomes ' 'from clinical samples by use of swift biosciences’ SARS-CoV-2 multiplex ' 'amplicon sequencing panel. J. Clin. Microbiol. 59, ' 'https://doi.org/10.1128/JCM.02226-20 (2020).', 'DOI': '10.1128/JCM.02226-20'}, { 'key': '32045_CR42', 'doi-asserted-by': 'publisher', 'unstructured': 'Lin, M. J., Shean, R. C., Makhsous, N. & Greninger, A. L. LAVA: a ' 'streamlined visualization tool for longitudinal analysis of viral ' 'alleles. bioRxiv, https://doi.org/10.1101/2019.12.17.879320 (2019).', 'DOI': '10.1101/2019.12.17.879320'}], 'container-title': 'Nature Communications', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41467-022-32045-1.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41467-022-32045-1', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41467-022-32045-1.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 7, 29]], 'date-time': '2022-07-29T19:07:19Z', 'timestamp': 1659121639000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41467-022-32045-1'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 7, 29]]}, 'references-count': 42, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['32045'], 'URL': 'http://dx.doi.org/10.1038/s41467-022-32045-1', 'relation': {}, 'ISSN': ['2041-1723'], 'subject': [ 'General Physics and Astronomy', 'General Biochemistry, Genetics and Molecular Biology', 'General Chemistry', 'Multidisciplinary'], 'container-title-short': 'Nat Commun', 'published': {'date-parts': [[2022, 7, 29]]}, 'assertion': [ { 'value': '1 March 2022', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '14 July 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '29 July 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'M.G.N. and G.R.P. are coinventors on patent 20190022116, ' 'N<sup>4</sup>-Hydroxycytidine and derivatives and anti-viral uses related ' 'thereto, covering composition of matter and method of use of EIDD-2801 for ' 'antiviral therapy. This study could affect their personal financial status. All ' 'other authors declare no competing interests.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '4416'}

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